Shifting the Risk-Benefit Ratio in CRC With Molecular Subtyping

Tara Petersen
Published: Sunday, Aug 16, 2015
John L. Marshall, MD

John L. Marshall, MD

Knowledge gained regarding molecular subtyping has led to an increased understanding of the diversity in colorectal cancer (CRC) tumors and the need for more nuanced treatment options. Recent evidence has shed some light on the prognostic value of microsatellite instability (MSI) and the potential benefit of checkpoint inhibition in CRC.

In addition, new evidence in the salvage setting has shown promise in extending survival.

However, knowing the best course of treatment in heavily pretreated patients with advanced CRC remains challenging. Treatment considerations in this population were the topic of discussion among a panel of experts during a recent OncLive Peer Exchange led by moderator John L. Marshall, MD.

Microsatellite Instability

Microsatellite instability (MSI) is caused by the loss of DNA mismatch repair (MMR) activity and is present in approximately 15% of all CRCs.1 Evidence has shown that tumors with a greater degree of genetic instability—MSI-high tumors—have a better prognosis and respond differently to chemotherapeutics than do tumors without MSI.1

Howard S. Hochster, MD

Howard S. Hochster, MD

The consensus is that MMR status is prognostic in stage II disease, Marshall noted, and that 5-fluorouracil (5-FU)–based therapy seems to be harmful in that setting. A retrospective analysis of data from the PETACC8 and NCCTG N0147 trials, however, showed that MMR was not prognostic in stage III patients.2 This analysis, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, was conducted in patients treated with FOLFOX, with or without cetuximab. The panel agreed that questions remain as to the utility of MMR status in stage III patients, but that it is still worthwhile to perform MSI tests on primary tumors.

Retrospective data are helpful in this setting, given that there is a paucity of prospective data on MSI in stage III CRC, stated Howard S. Hochster, MD.

“If [retrospective data] tells us that we need to treat the MMR mismatch repair enzyme-deficient patients in stage III with the same treatment and [that] they have the same benefit, that’s already reasonable information,” Hochster said. “It’s an area where we’ve wondered what to do, so I feel more reassured when I see a patient like that that we’re making a good recommendation based on real data.”

The incidence of MMR enzyme deficiency lessens in later stages; Hochster approximated it at 15% in stage II, 7% to 8% in stage III, and 4% in stage IV. At his institution, regardless of the stage of cancer, “every colon resection is reflexively tested for MMR deficiency by immunohistochemical staining.” There are other confounding factors influencing prognosis, such as Lynch syndrome and RAF mutations. Studies have suggested that chromosomal aberrations may be different in stage II and stage III, and this may help explain why 5-FU is associated with poorer outcomes in stage II disease, stated Richard M. Goldberg, MD. “As we [understand] the importance of immune checkpoints, it may be that part of that explanation is that we’re killing the wrong cells,” Goldberg said. “We’re killing those lymphocytes that are helping to contain micrometastatic disease.” He added that he often prefers FOLFOX to 5-FU in MSI-high patients.

Richard M. Goldberg, MD

Richard M. Goldberg, MD

Checkpoint Inhibitors

Checkpoint inhibition has shown promise in traditional immunologically active cancers, such as kidney cancer and melanoma. More recently, agents targeting immune checkpoints such as programmed death-1 (PD-1) and its ligand, PD-L1, have demonstrated efficacy in lung cancer and bladder cancer.

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